Project Summary A group of orbital inflammatory diseases, including thyroid eye disease (TED), granulomatosis with polyangiitis (GPA), sarcoidosis, and nonspecific orbital inflammation (NSOI) constitutes an important cause of vision loss, pain, and diplopia. Clinical data with histopathology are sufficient to make a diagnosis for some patients but not for others. Gene expression profiling has proven useful in the diagnosis of several cancers and other inflammatory diseases. Specific hypotheses to be tested include that: (1) tissue from patients with TED does not display nearly as much immune related activity as tissue from patients with GPA, sarcoidosis, or NSOI, even if the TED samples are derived from muscle or from patients with new onset disease; (2) specific inflammatory diseases affecting the lacrimal gland have distinct molecular signatures; (3) an algorithm based on a limited number of transcripts expressed in orbital tissue or peripheral blood can supplement or replace orbital biopsies; (4) a subset of patients with NSOI has a disease that can be distinguished from GPA, sarcoidosis, and TED by molecular profiling. The results from this study are changing the understanding of the pathogenesis of each of these diseases. This improvement in classification/diagnosis and in understanding pathogenesis has the potential to lead to improvement in therapy and outcome.